DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 11, 13, 15, 16, 22 and 24-38 are pending in this application and were examined on their merits.
The rejection of Claim(s) 11, 13, 15, 24, 25, 27, 28, 29, 32, 33, 34, 35, 36 and 38 are rejected under 35 U.S.C. § 103 as being unpatentable over Konrath et al. (US 7,718,380 B2), of record, in view of Zhuo et al. (WO 2015/123598 A1), cited in the IDS, Yang et al. (1997), Terzi et al. (US 2015/0258127 A1) and Jiang et al. (2016), and further in view of Wei et al. (US 7,790,401 B2) and Randolph et al. (US 2017/0065707 A1), both of record, has been withdrawn due to the Applicant’s amendments to Claims 34-36 filed 05/01/2026.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 11, 13, 15, 22, 24, 25, 27, 28, 29, 32, 33, 34, 35, 36 and 38 are newly rejected under 35 U.S.C. § 103 as being unpatentable over Konrath et al. (US 7,718,380 B2), of record, in view of Zhuo et al. (WO 2015/123598 A1), cited in the IDS, Yang et al. (1997), Terzi et al. (US 2015/0258127 A1) and Jiang et al. (2016), all of record, as necessitated by Applicant’s amendment to Claims 34-36 filed 05/01/2026.
Konrath et al. teaches a composition/system comprising: a patient tacrolimus (whole) blood sample mixed with a hemolytic/extraction agent containing a detergent mix of the 1.0% TRITON® X-100 (octylphenoxypolyethoxy. ethanol) and 0.5% deoxycholate (Column 7, Lines 16-29), and reading on Claims 11, 22, 24, 27, 28, 32 and 33.
With regard to Claims 11, 24, 28 and 34, 35, 36, Konrath et al. further teaches,
"In general, the concentration of detergent should be in the range of about 0.1% to about 3.0% w/v, and preferably about 0.3% to about 1.0%, during the RBC lysis step, and the concentration of extracting agent (deoxycholate or other aqueous detergents) should be in the range of about 0.3% to about 1%, preferably about 0.4% to about 0.6% during the extraction step" (Column 5, Lines 12-23).
Thus, the composition of Konrath et al. either anticipates the claim limitations of "about 0.05-0.25% deoxycholate" and “the ratio of octylphenoxypolyethoxy ethanol to deoxycholate is 4:1 or 1.0:0.25%) as the reference taught amount of 0.5% deoxycholate would be considered "about" or "approximately" 0.25% (lacking a definition for "about" in the Specification and giving the term its' broadest, reasonable interpretation) or in the alternative, the limitation is made obvious by the reference disclosure of "about 0.3-1.0% and “about 0.4-0.6%” extracting agent (deoxycholate or other aqueous detergents)" which would overlap and obviate the claimed concentration range. See the MPEP at 2144.05, I.
With regard to Claims 11 and 38, Konrath et al. further teaches that tacrolimus forms complexes with other blood plasma constituents such as immunophilins, albumin and lipoproteins and in order to assay tacrolimus the tacrolimus/protein complexes must be dissociated to release tacrolimus (Column 1, Lines 47-53).
The teachings of Konrath et al. were discussed above.
Konrath et al. did not teach that the composition further comprises anti-Lp-PLA2 antibodies (binding molecules), as required by Claims 11, 13, 24, 25 and 28;
or that the sample is a serum sample, as required by Claims 11 and 38.
Zhuo et al. teaches a method of diagnosing cardiovascular disease (CVD) in a subject based on the level of Lp-PLA2 (Abstract);
an anti-Lp-PLA2 antibody (Pg. 22, Paragraph [0096]); and that detergent can readily make Lp-PLA2 from a biological sample, such as a blood sample available for assay (e.g. may dissociate Lp-PLA2 from the lipoproteins LDL and HDL) (Pg. 18, Paragraph [0078]).
Yang et al. teaches that blood serum contains both albumin and lipoprotein (Pg, 507, Abstract).
Terzi et al. teaches the determination of tacrolimus serum levels by radioimmunoassay (Pg. 9, Paragraph [0103]).
Jiang et al. teaches that Lp-PLA2 is found in (blood) serum (Pg. 5, 3rd Paragraph).
It would have been obvious to those of ordinary skill in the art before the invention to modify the composition/system of Konrath et al. comprising a tacrolimus patient (whole) blood sample mixed with a hemolytic/extraction agent containing 1.0% of the detergent TRITON® X-100 and 0.5% (or about 0.25%) of the detergent deoxycholate to modify the method to use a blood serum sample because Konrath further teaches that tacrolimus forms complexes with other blood plasma constituents such as immunophilins, albumin and lipoproteins and in order to assay tacrolimus the tacrolimus/protein complexes must be dissociated to release tacrolimus.
Terzi et al. teaches that blood serum may be used to assay tacrolimus in blood serum and Yang et al. teaches that blood serum contains both lipoprotein and albumin. Those of ordinary skill in the art would have recognized that blood serum, in addition to whole blood and plasma, may be used as a sample to assay tacrolimus. However, as taught by Konrath above, before assay the tacrolimus must be dissociated from complex with proteins (such as albumin and lipoprotein) found in the blood serum. Those of ordinary skill in the art would have been motivated to make this modification to assay tacrolimus in a patient blood serum sample based on the availability of samples and artisan preference. There would have been a reasonable expectation in making this modification because tacrolimus can be assayed in both whole blood, plasma and serum.
It would have been further obvious to those of ordinary skill in the art before the invention to modify the composition/system of Konrath et al., Yang et al. and Terzi et al. comprising a tacrolimus patient serum sample mixed with a hemolytic/extraction agent containing 1.0% of the detergent TRITON® X-100 and 0.5% (or about 0.25%) of the detergent deoxycholate with the addition of an anti-Lp-PLA2 antibodies (binding molecules) as taught by Zhuo et al. because this would provide a composition which would also enable detection of Lp-PLA2 in the tacrolimus serum sample. Jiang et al. teaching that blood serum contains Lp-PLA2. Those of ordinary skill in the art would have been motivated to make this modification in order to additionally assess the tacrolimus patient serum sample for a biomarker of cardiovascular disease. There would have been a reasonable expectation of success in making this modification because Konrath et al. teaches the use of a detergent mix as a hemolysis/extraction agent to dissociate tacrolimus from protein in a blood sample, Zhuo et al. teaches that detergent makes Lp-PLA2 in blood sample available for assay and Jiang et al. teaches that blood serum also contains Lp-PLA1.
With regard to the limitations of Claims 11, 15, 28 and 29, it would be inherent in the composition/system of Konrath et al. that the amount of detergent in the detergent/blood mixture would result in 5% or less and/or 0.1-1% or less of the Lp-PLA2 molecules in the blood sample being associated with said lipoprotein samples because the prior art teaches blood mixed with 1.0% TRITON® X-100 and 0.5% deoxycholate (making obvious the claimed range of about 0.05-0.25% deoxycholate) and the Specification teaches that these amounts are embodiments of the claimed invention. The Specification teaches that as samples are incubated with increasing
concentrations of TRITON® X-100 up to 1% and deoxycholate up to 0.5%, more Lp-
PLA2 is liberated until it plateaus at those maxima (Specification as filed, Pg. 9, Lines
15-21 and Fig. 5). The Specification as filed further teaches at Pg. 12, Lines 15-16 that
an exemplary embodiment of the invention (CHL sample diluent) produces an estimated
greater than 95% of released Lp-PLA2. Therefore, the prior art composition would be
expected to have the same effects and results as the claimed invention.
With regard to Claims 24 and 27, it would have been obvious to those of ordinary
skill in the art before the invention to compile of all the components as claimed into a
single location to create a de facto "kit" because this would provide the practitioner with
all of the components to practice the method in one discrete location. Those of ordinary
skill in the art would have been motivated to make this modification in order to eliminate
the need to track down and/or retrieve individual assay components.
There would have been a reasonable expectation of success in making this modification because the prior art provides all of the claimed components and compiling them into a discrete location would have been within the skill and purview of those of ordinary skill in the art.
Claim(s) 11, 13, 15, 16, 24, 25, 27, 28, 29, 30, 32, 33, 34, 35, 36 and 38 are rejected under 35 U.S.C. § 103 as being unpatentable over Konrath et al. (US 7,718,380 B2), of record, in view of Zhuo et al. (WO 2015/123598 A1), cited in the IDS, Yang et al. (1997), Terzi et al. (US 2015/0258127 A1) and Jiang et al. (2016), all of record, as applied to Claims 11, 13, 15, 24, 25, 27, 28, 29, 32, 33, 34, 35, 36 and 38 above, and further in view of Jardine (2005), of record.
The teachings of Konrath et al., Zhuo et al., Yang et al., Terzi et al. and Jiang et al. were discussed above.
None of the above references taught wherein the sample is from a patient suspected of having, or diagnosed with cardiovascular disease (CVD), as required by Claims 16 and 30.
Jardine teaches that renal transplant patients being treated with tacrolimus have increased risk for CVD (Pg. 380, Column 1, Lines 25-31).
It would have been obvious to those of ordinary skill in the art before the invention that the composition/system of Konrath et al., Zhuo et al., Yang et al., Terzi et al. and Jiang et al. comprising a tacrolimus patient blood serum sample, that the sample be obtained from a patient suspected of having or having CVD, such as a renal transplant patient, because Jardine teaches that renal transplant subjects treated with tacrolimus are at increased risk of CVD. Those of ordinary skill in the art would have been motivated to make this modification because tacrolimus treated renal transplant patients are at risk of having or developing CVD, therefore the ordinary artisan would recognize that this patient population would be at increased risk of having or developing CVD, which should be screened for. There would have been a reasonable expectation of success in making this modification because Konrath et al. teaches the use of tacrolimus treated blood sample and Jardine teaches an association between CVD and tacrolimus treated renal transplant patients.
Claim(s) 11, 13, 15, 24, 25, 26, 27, 28, 29, 31, 32, 33, 34, 35, 36, 37 and 38 are rejected under 35 U.S.C. § 103 as being unpatentable over Konrath et al. (US 7,718,380 B2), of record, in view of Zhuo et al. (WO 2015/123598 A1), cited in the IDS, Yang et al. (1997), Terzi et al. (US 2015/0258127 A1) and Jiang et al. (2016), all of record, as applied to Claims 11, 13, 15, 24, 25, 27, 28, 29, 32, 33, 34, 35, 36 and 38 above, and further in view of Wolfert et al. (US 2007/0281323 A1), of record.
The teachings of Konrath et al., Zhuo et al., Yang et al., Terzi et al. and Jiang et al. were discussed above.
None of the above references taught a composition/kit wherein the anti-Lp- PLA2 antibodies are bound to latex microparticles, as required by Claims 26, 31 and 37.
Wolfert et al. teaches a method wherein an Lp-PLA2 containing sample is contacted with an immobilized binder, which specifically binds Lp-PLA2, wherein the immobilized binder is an antibody (Pg. 29, Claims 1 and 3);
and wherein the immobilized binder is bound to a latex bead (Pg. 6, Paragraph [0059]).
The Wolfert reference further teaches that immobilization allowed for a washing step to remove any unbound material or interfering substances (Pg. 6, Paragraph [0060]).
It would have been obvious to those of ordinary skill in the art before the instant invention to modify the composition/system of Konrath et al., Zhuo et al., Yang et al., Terzi et al. and Jiang et al. comprising a patient blood serum sample mixed with a hemolytic/extraction agent containing 1.0% TRITON® X-100 and 0.25% deoxycholate and further comprising anti-Lp-PLA2 antibodies with the immobilization of those antibodies to a latex bead as taught by Wolfert et al., because this would allow for the isolation of Lp-PLA2 in the blood serum sample. Those of ordinary skill in the art before the instant invention would have been motivated to make this modification because the immobilizing allows for a washing step to remove any unbound material or interfering substances.
While the Wolfert et al. reference does not indicate that the latex beads are "microparticles", the mere change in size of the latex particles is not sufficient to render them non-obvious as they would still function the same as the prior art latex particles. See the MPEP at 2144.04, IV. A. There would have been a reasonable expectation of success in making this modification because at least both Zhuo et al. and Wolfert et al. are drawn to the use of anti-Lp-PLA2 antibodies.
Response to Arguments
Applicant's arguments filed 05/01/2026 have been fully considered but they are not persuasive.
The Applicant argues that Claim 11 requires that the two or more detergents comprise TRITON™ X-100 (octylphenoxypolyethoxy ethanol) and from about 0.05-0.25% deoxycholate and the selection of the particular detergents would not have been obvious. Applicant asserts that deoxycholate (steroid detergent) and TRITON™ X-100 increased Lp-PLA2 immunodetection over a similar sample treated with CHAPS (steroid detergent) alone (Remarks, Pg. 7, Lines 7-36 and Pg. 8, and Pg. 9, Lines 1-22).
This is not found to be persuasive for the following reasons, as discussed above and in the prior action, Konrath specifically teaches a composition containing a detergent mix of 1% TRITON™ X-100 and 0.5% deoxycholate, and therefore the selection of the detergent mixture would have been highly obvious.
Konrath et al. further teaches,
"In general, the concentration of detergent should be in the range of about 0.1% to about 3.0% w/v, and preferably about 0.3% to about 1.0%, during the RBC lysis step, and the concentration of extracting agent (deoxycholate or other aqueous detergents) should be in the range of about 0.3% to about 1%, preferably about 0.4% to about 0.6% during the extraction step" (Column 5, Lines 12-23).
Thus, the composition of Konrath et al. either anticipates the claim limitation of "about 0.05-0.25% deoxycholate" as the reference taught amount of 0.5% deoxycholate would be considered "about" or "approximately" 0.25% (lacking a definition for "about" in the Specification and giving the term its' broadest, reasonable interpretation) or in the alternative, the limitation is made obvious by the reference disclosure of "about 0.3-1.0% and “about 0.4-0.6%” extracting agent (deoxycholate or other aqueous detergents)" which would overlap and obviate the claimed concentration range. See the MPEP at 2144.05, I.
That the claimed detergent mixture of TRITON™ X-100 and deoxycholate (which is the same as the prior art) produced better Lp-PLA2 detection over the use of a single detergent (CHAPS) alone, is neither surprising or unexpected as similarly to Lp-PLA2, the tacrolimus of Konrath is also complexed with blood plasma protein components and must be treated with detergent to dissociate from the protein before assay. Thus, the ordinary artisan would reasonably expect that treatment with two detergents would produce better dissociation than treatment with a single detergent.
The Applicant argues that the TRITON™ X-100 and deoxycholate act synergistically, citing Pg. 9, Lines 11-25 of the filed Specification and Fig. 5 wherein serum samples were treated with increasing amounts of TRITON™ X-100 or deoxycholate and assayed for Lp-PLA2 wherein increasing amounts yielded increased Lp-PLA2 (of about max 125ng/mL Lp-PLA2 at 0.5% detergent). Applicant asserts that the ordinary artisan would therefore have expected a yield of 250 ng/mL and not the about 750 ng/mL yield depicted in Fig. 8 (Remarks, Pg. 9, Lines 23-36 and Pg. 10).
This is not found to be persuasive for the following reasons, as discussed above, the prior art already recognized the same problem as Applicant (that the target component in a blood sample is complexed with blood proteins and must be dissociated from then to be assayed) and provided a solution to said problem (treating the blood sample with a mixture of TRITON™ X-100 and deoxycholate). Applicant asserts a “synergistic” effect, however Applicant has not provided evidence that the alleged effect is seen over the entire claimed range (e.g. Fig. 8 is drawn to serum samples treated only with 1% TRITON™ X-100 and 0.5% deoxycholate, which are the same amounts taught by Konrath) and the claims are drawn to an unspecified amount of octylphenoxypolyethoxy ethanol and about 0.05-0.25% deoxycholate. Thus, the alleged unexpected showing is also not commensurate in scope with the claimed invention and further does not represent a comparison with the closes prior art, which would be the detergent composition of Konrath.
The Applicant argues that the Konrath teaches tacrolimus is bound to FK binding proteins which must be lysed using the described hemolytic agent and does not teach or suggest that tacrolimus can be dissociated from serum components such as albumin and lipoproteins using the detergent mixture (Remarks, Pg. 11, Lines 8-30 and Pg. 12).
This is not found to be persuasive for the following reasons, Konrath clearly teaches at Column 1, Lines 42-53:
“Tacrolimus is extensively sequestered in erythrocytes (red blood cells or RBCs), bound to FK binding protein (FKBP; therefore, whole blood samples are a preferred matrix for therapeutic blood monitoring of tacrolimus, even if it can be extracted form biopsies samples, bone marrow and other body fluids. Tacrolimus also forms complexes with other blood plasma constituents such as immunophilins, albumin and lipoproteins. In order to determine the presence of tacrolimus and its concentration in a human blood sample, RBC's present in the sample must be lysed to release the tacrolimus/protein complexes. Then the tacrolimus/protein complexes must be dissociate to release tacrolimus”.
Thus, the reference recognizes that tacrolimus is complexed with FKBP and forms complexes with other blood plasma components, such as immunophilins, albumin and lipoproteins and in order to assay tacrolimus, RBCs must be lysed to release the tacrolimus/protein complexes (whether FKBP, immunophilins, albumin and/or lipoproteins) which then must be dissociated to release tacrolimus. Konrath specifically teaches at Column 3, Lines 17-20 that:
The extraction agent dissociates or releases tacrolimus from its complex with blood protein components into an aqueous solution compatible with subsequent quantification assay methods.
Konrath further teaches a hemolytic/extraction agent comprising 1% TRITON™ X-100 and 0.5% deoxycholate at Column 7, Lines 25-28).
Thus, the ordinary artisan would readily recognize that the detergent composition of Konrath would both lyse red blood cells as well as dissociate protein (including blood protein) complexed tacrolimus for assay.
The Examiner notes that the Applicant did not specifically address the teachings of Zhuo et al. (WO 2015/123598 A1), cited in the IDS, Yang et al. (1997), Terzi et al. (US 2015/0258127 A1) and Jiang et al. (2016), Jardine (2005) or Wolfert et al. (US 2007/0281323 A1) all of record.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
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If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653
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